This project is based upon the hypothesis that the cellular redox status plays a critical role in preventing vascular cell dysfunction that is related to the initiation and progression of atherosclerosis. Oxidative stress has been implicated as an etiologic factor in atherosclerosis and its clinical manifestations, and therefore, antioxidants may have anti-atherogenic properties and may reduce the morbidity and mortality from coronary heart disease. Since endothelial activation is one of the initiating events in atherosclerosis and has been related to oxidative stress through specific redox sensitive processes, intracellular antioxidants may affect the response of endothelial cells to oxidative stress or inflammatory cytokines, and be of therapeutic potential in pathologies related to endothelial dysfunction. Previous studies have evaluated the effects of the antioxidant lipoic acid (LA) on vascular redox sensitive processes in cultured cells in vitro; however, little is known about the role of LA in endothelial activation in vivo. Therefore, the overall objective of this project is to determine the role of LA in oxidative stress-induced endothelial activation and atherosclerosis in vivo. Specific aim 1 will determine the role of cellular LA in endothelial activation in mice challenged with cytokines or bacterial endotoxin lipopolysaccharide (LPS). In vivo oxidative stress will be monitored and the expression of adhesion molecules and monocyte chemoattractant protein-l (MCP-1) will be determined. Mechanisms for observations will be further addressed including gene regulation and nuclear factor-kappaBeta (NFkB) activation. Specific aim 2 will determine the role of LA in atherosclerotic lesion development in an ApoE knockout mouse model. Plasma cholesterol levels will be examined and atherosclerotic plaque areas will be quantified at the aortic origin. The work contained in this proposal will provide new insights into the effectiveness of LA treatment to inhibit the earliest stages of atherosclerotic lesion development and will be integrated in the long-term objectives to examine the potential of LA to lower coronary risk in humans by dietary supplementation. Taken together, the studies of this proposal will contribute to the understanding of the mechanisms by which cellular antioxidant status is important in the maintenance of vascular homeostasis and, thus, provide new targeted strategies for the prevention and treatment of atherosclerosis and other inflammatory diseases.